Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Cancer gene therapy using a cytokine, IL-12 and a costimulatory signal molecule B7.1 (Meeting abstract).
Proc Annu Meet Am Soc Clin Oncol; 14:A583 1995. Unique Identifier : AIDSLINE ICDB/95613736 Zitvogel L; Tahara H; Robbins PD; Davis G; Lotze MT; Univ. of Pittsburgh, Pittsburgh, PA 15261
Abstract:
IL-12 is a heterodimeric cytokine produced by macrophages and B lymphocytes with important regulatory functions in vitro and in vivo. It directly stimulates activated NK and T cells to produce high levels of IFN gamma, enhances their cytolytic activity and promotes maturation of Th1 cells. IL-12 is a critical agent to induce cell mediated immunity in some infectious diseases and promotes potent antitumor effects in weakly immunogenic murine tumor models following systemic administration. We have tested paracrine delivery of IL-12 using autologous or allogeneic fibroblasts engineered to secrete high levels of IL-12 as a gene therapy to treat 4 to 8 day-established murine tumors, at the same or at a distant site from the therapeutic injection, and to elicit a long term and specific antitumor immunity. Injection of IL-12 engineered fibroblasts at the site of an established (day 8) MCA207 sarcoma could efficiently eliminate or suppress tumor growth in a dose dependant manner. Weekly inoculations for three weeks could also be used to effectively treat a day 3-4 sarcoma located intradermally in the opposite flank (80% using autologous fibroblasts), resulting in long term protective antitumor immunity. In less immunogenic models (MCA 102, MC38), 7 day-established lung metastases could be significantly reduced synergistically with systemic administration of low doses of IL-2. Histologic findings included a mixed infiltrate of CD4+ and CD8+ T effectors and macrophages in the regressing sarcoma on day 21. No outward signs of toxicity was observed in these mice treated with weekly injections of IL-12 modified syngeneic fibroblasts. IL-12 engineered fibroblasts appear to serve the function of an IL-12 delivery system, more than that of a tumor vaccine component, in these three tumor models. Interestingly, in less immunogenic tumor models (TSA, mouse breast adenocarcinoma), the expression of the costimulatory signal molecule B7.1 on tumor cells or fibroblasts can enhance IL-12 mediated antitumor immunity in establishment as well as therapeutic models in vivo. Tumor rejection after direct costimulation of T cells by B7.1 expressing tumor cells admixed with IL-12 producing counterparts is abrogated by CTLA4Ig, and systemic administration of anti-IFN gamma or TNF alpha antibodies. Finally, we have recently been approved by the NIH Recombinant DNA Advisory Committee to perform a clinical protocol utilizing IL-12 transfected autologous fibroblasts which will be directly injected into accessible neoplastic sites in solid tumors.
Keywords: Animal CD4-Positive T-Lymphocytes/IMMUNOLOGY CD8-Positive T-Lymphocytes/IMMUNOLOGY Fibroblasts/TRANSPLANTATION *Gene Therapy *Immunotherapy Interleukin-12/*ADMINISTRATION & DOSAGE/*BIOSYNTHESIS/GENETICS Mice Sarcoma, Experimental/IMMUNOLOGY/*THERAPY Transplantation, Autologous Transplantation, Homologous ABSTRACT 951230
M95C3228
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
